Indications for Transplant in Low/Intermediate Risk MDS

At the 2019 Lymphoma & Myeloma Congress, Koen van Besien, MD, PhD, Weill Cornell Medicine & NewYork-Presbyterian Hospital, New York, NY, discusses data on the indications for transplant for patients with low and intermediate-grade MDS.

Transcript

I am Dr. Koen van Besien. I'm a professor of medicine at Weill Cornell in New York, and I'm the director of the stem-cell transplant unit at NewYork-Presbyterian/Weill Cornell.

Today, I presented data on the indications of transplant for patients with low and intermediate-grade MDS. MDS is a chronic disorder that often occurs in the 6th decade of life, but many times earlier. We see patients in their 40s, patients in their 50s, and then increasingly 60s, and 70s.

It is treatable. It is incurable unless one performs a stem-cell transplantation. There's various types of MDS, and those with low or intermediate-grade MDS tend to have a more indolent course. Their survival is measured in years rather than in months with conventional therapy.

The question often arises what is the best approach for individual patients. Should we subject them to transplant that can cure them but that also can have fatal complications as well as chronic complications, or should we try to support them with a medical treatment or with supportive care that is not curative?

It's a very complex issue. Every patient is different. There are some guidelines that have been put forward by panels of experts, and in general, those experts recommend not to transplant patients immediately upon diagnosis.

Why not? Because the toxicity of transplant outweighs the benefits of the transplant, and there's more patients we harm by transplants than helping them. These expert opinions are always in flux. They're often based on data from 10 years ago, and they do not necessarily represent our feeling today.

What has happened over these 10 years is that, one, conventional treatment, supportive care interventions to improve the blood counts in those patients have improved thanks to many research efforts.

At the same time, the outcomes of transplants have gradually improved, and we now can offer transplants to patients who formerly would have been thought ineligible, and we have also better results and fewer complications.

I presented 2 cases. One was a patient who was diagnosed with MDS, a subtype called MDS with ring sideroblasts at age 61. She was felt not to need a transplant immediately upon diagnosis.

She was treated with a variety of treatments, erythropoietin, later on lenalidomide, and even low dose chemotherapy, a hypomethylating agent called azacytidine. She didn't respond to any of those, and therefore, she was brought to transplant at that time.

That brings me to the point that there are patients with low and intermediate-risk MDS who do benefit from transplant, and where there's a consensus that transplant should be offered.

Those are the ones who fail initial treatments or no longer respond, those that have low counts, low platelets, and low hemoglobin and needing transfusions, low white counts, low neutrophil counts, and being at risk for infections.

Also, certain cytogenetic abnormalities or an increase in blasts or certain molecular abnormalities, particularly P53 and ASXL1 may constitute the indications for immediate transplant. In this patient we recommend a transplant because of failure to respond to initial treatments.

The audience asked “why not try more additional treatments to try and rescue her and to keep her going?” That would have been a reasonable option. The new drug luspatercept was brought up. Luspatercept will soon be approved for treatment of anemia.

There have reasonable approach to treat this patient with luspatercept to relieve her anemia, which was the main symptom. That said, such drug interventions would not have cured her, and might have helped her for a couple of years, but then, the same question would have come up.

How long can we treat her? What are the chronic complications and the expenses of these drug interventions? What are the chances with the transplant? That is also a complicated issue. What are the chances of cure with the transplant?

A lot depends on the health of the patient, and that is where we have made progress in transplantation. We no longer consider age over 60 a contraindication. We no longer consider comorbidities, at least the slowest. They are moderate or limited in extent contraindications.

We have the option to remedy a lot of the comorbidities prior to transplant. In this patient, after careful evaluation and assessment of risks, we felt that she was an excellent candidate. We then went on to identify a donor.

It is important in this disease to remind the physicians that there are a number of donors types. There's matched siblings, there's also HLA identical unrelated donors, and increasingly, there are so-called alternative donors including haplo donors, partially matched family donors, cord blood donors or combinations of these haplo and cord blood donors, as we practice at Cornell.

The latter procedures, these alternative donors, have much improved over the past 5 years. Outcomes, including survival and rates of graft-versus-host-disease now approach those sibling transplant and of HLA identical unrelated donor transplantation.

They are, however, not exactly as excellent yet. They're still approximately 10% inferior, and therefore in a disease such as this, where there's no urgency, and myelodysplastic syndrome is not a very aggressive disease.

There's often ways to wait a month or 2 to try and identify the best donor. We very much urge patients to do that and to wait until the best donor has been identified. Such a donor may well be that mismatched donor, but if there's a perfectly matched unrelated donor, that remains our preference.

Last issue that I discussed was the issue of the patient who has an infuse percentage blasts. For those patients, there's consensus that the transplant is indicated, because there's a constant concern over rapid evolution to acute leukemia.

It's been customary to induce those patients with either hypomethylating agents or with intensive chemotherapy or more recently with drugs such as the new CPX drug. Data are not very supportive of this.

There are a number of retrospective data from various groups, groups in Germany, groups in Italy, the Seattle group, again and again suggesting that current methods of induction, and at times that's reducing blasts prior to transplant, may well result in elimination of high-risk patients rather than improvement in the outcomes of transplant.

That may well be true for the current conventional drugs used for induction of remission. Should we induce patients with excess blasts prior to transplant?

We continue to do so, particularly since there's an increasing number of novel drugs that have minimal toxicity and that may lead to very profound deep remissions prior to transplant, which likely more than the reduction in percentage blasts contribute to improved long-term survival.

In summary, I explained to the audience that patients with low and intermediate-risk MDS should be offered transplant if they have risk factors in addition to their presentation. These risk factors may include the cytogenetics, they may include the percentage blasts, they may include pancytopenia or the cytopenia.

They may include molecular abnormalities, such as P53 and ASXL1. They may also be failure of other treatments.

Lastly, while this is the standard, and while we support this standard, it is possible that as transplant continues to improve, that outcomes of transplant, particularly in early-stage patients, may become so excellent that we may move transplant earlier in the treatment of this disease.